Midbrain dopaminergic (DAergic) neuronal loss is a pathological hallmark of Parkinson's disease (PD). The cause and mechanisms underlying the loss of DAergic neurons in Parkinson's disease are poorly understood. Several lines of evidence indicate that Nurr1, a member of nuclear receptor super family, may have important role in regulating survival of DAergic neurons in Parkinson's disease. Specifically: (1) Nurr1 is highly expressed in the midbrain DAergic system. (2) Nurr1 is essential for the induction of developing midbrain DAergic neurons. (3) Nurr1 may be critical for the survival of DAergic neurons in adulthood. Reduced Nurr1 expression in adult heterozygous (Nurr1 +/-) mice or in aged wild-type mice is associated with increased vulnerability to selective DAergic neurotoxin MPTP. The applicant proposes that Nurr1 gene expression plays an important role in maintaining mature DAergic neuron function and decreased Nurr1 expression resulting from aging, genetic defects, and/or environmental factors may increase the vulnerability of DAergic dysfunction, as in Parkinson's disease. Specific Aims are proposed to investigate if Nurr1 gene is a susceptibility factor for declined DAergic function in animal models of Parkinson's disease and in patients with Parkinson's disease. Investigator will (1) delineate the association of age-related decrease in Nurr1 expression and reduction in DA levels in nigral-striatal pathway; (2) determine the vulnerability of heterozygous Nurr1-deficient mice and aged mice with reduced Nurr1 expression to MPTP; (3) evaluate the protective role of increased Nurr1 expression against DAergic neuron degeneration; and (4) determine whether Nurr1 gene expression is reduced in the brains of patients with Parkinson's disease. This proposed study will improve our understanding of the mechanism of Nurr1 gene in the selective DAergic neuron degeneration and may yield information that will help define its role in the pathogenesis of Parkinson's disease, and provide molecular basis for developing novel therapy for this devastating disease.